| Literature DB >> 32168746 |
José E S Nunes1,2, Mario A Duque1,3, Talita F de Freitas1,2, Luiza Galina1,2, Luis F S M Timmers4, Cristiano V Bizarro1,3, Pablo Machado1,3, Luiz A Basso1,2,3, Rodrigo G Ducati1,4,5.
Abstract
Roughly a third of the world's populatioical">n is estimated to have latentEntities:
Keywords: Mycobacterium tuberculosis; enzyme drug target; enzyme inhibition; human tuberculosis; rational drug design; shikimate pathway
Mesh:
Substances:
Year: 2020 PMID: 32168746 PMCID: PMC7144000 DOI: 10.3390/molecules25061259
Source DB: PubMed Journal: Molecules ISSN: 1420-3049 Impact factor: 4.411
Figure 1The shikimate pathway. The gene coding for each enzyme is in parenthesis. * Spontaneous cyclization of 3-deoxy-d-arabino-heptulosonate 7-phosphate (DAHP). Pi = inorganic phosphate.
Figure 2Chorismate: a metabolic node.
Figure 3Overall proposed chemical mechanism of condensation of PEP with E4P. H-enz = H-enzyme.
Figure 4The structure of MtDAHPS. (a) Structure of the MtDAPHS tetramer showing monomeric units. Mn2+ ions at the MtDAHPS active site are shown as purple spheres. (b) Active site of MtDAHPS showing the interactions with the PEP substrate (orange and purple stick model). The images were generated on PyMOL.
Figure 5Linear chemical structures of MtDAHPS inhibitors. (a) simplified bisphosphate, (b) 3-pyridine carboxyaldehyde, (c) α-tocopherol, (d) rutin.
Figure 6Multi-step reaction catalyzed by MtDHQS.
Figure 7Structure of IMB-T130, a MtDHQS inhibitor.
Figure 8Structure of selected inhibitors of MtDHQase. (a) Molecule generated by virtual screening extracted from Petersen and coworkers [69]. (b) Example of nanomolar competitive inhibitor extracted from Tizón and coworkers [79]. *MIC obtained with the n-propil ester prodrug. (c) Natural occurring molecule (Narigin) found by virtual screening by Lone and coworkers [81].
Figure 9MtSD (a) kinetic and (b) chemical mechanisms. R represents the ribose, adenosine diphosphate and 2′-phosphate moieties of NADPH.
Figure 10Examples of inhibitors of MtSD. (a) Triazolothiadiazole IMB-SD62, inhibitor of MtSD, extracted from Li and coworkers [111,113]. (b) and (c) S. aureus SD inhibitors extracted from Enríquez-Mendiola and coworkers [110]. (d) Polyphenolic, inhibitor of P. putida SD, extracted from Peek and coworkers [108].
Figure 11Overall MtSK structure. The image was generated on PyMOL.
Figure 12The kinetic mechanism of MtSK.
Figure 13Chemical structures of the top scoring compounds inhibiting MtSK identified from different studies. (a) [123,128]; (b) [117]; (c) [129]; (d) [126].
Figure 14Graphical representation of MtEPSPS tertiary structure in complex with S3P and PEP. The image was generated on PyMOL.
Figure 15General reaction of EPSPS with the particular tetrahedral intermediate.
Figure 16Scheme of the proposed mechanism of catalysis for EPSPS [139].
Figure 17Graphical representation MtCS quaternary structure. The image was generated on PyMOL.
Figure 18Proposed catalytic mechanism for the CS reaction based on quantum mechanics/molecular mechanics (QM/MM) with the interaction of aspartic acid 339 (D339).